Cerebellum - development

Its three-layered cortex and well-defined afferent and efferent fiber connections make the cerebellum a favorite field for research on development and fiber connections of the central nervous system.

Illustrations for this section can be found in J Neurol(2003)250:1025–1036

 

Morphogenesis

The cerebellum arises bilaterally from the alar layers of the rhombomere in a structure known as tuberculum cerebelli which consists of a band of tissue in the dorsolateral part of the alar plate. It looks like an inverted ‘V’, where the arms of the ‘V’ direct caudally and laterally and then thickens and bulges downwards into the 4th ventricle to give rise to the internal cerebellar bulge. During the 7th week in development it bulges outwards forming external cerebellar bulges which represent the flocculi. The rostral midline part remains small, but in the 3rd month its growth accelerates and fills the gap between the limbs of the ‘V’, forming the vermis. By the 13th week, the outward, lateral and rostral growth processes reshape the cerebellum to a transversely orientated bar of tissue over the 4th ventricle. At the 12th week of development, fissures form transversely to the longitudinal axis from the vermis and then spread laterally.

                  

Cerebellar cortex histogenesis

The main cell types of the cerebellum arise at different times of development and at different locations.

Main output neurons from the cerebellar cortex are the Purkinje neurons that are generated early in the cerebellar development and form a one cell thick layer throughout the cerebellum. They are generated from the ventricular zone (which expresses bHLH factor Ptf1a) near the 4th ventricle of brainstem (similar to neuronal development in cerebrum). After the final mitotic division, the Purkinje cells migrate and accumulate as the cerebellar plate. Other cerebellar interneurons such as Golgi, stellate and basket cells also arise from the ventricular zone of the metencephalic alar plates (these are the GABAergic cerebellar neuronal subtypes which constitute the main outflow tract of the cerebellum.)

Purkinje cells migrate along radial glial cells to their future position using the reelin-dependant pathway. Axons of Purkinje cells extend straight, whereas granule cell axons become T-shaped after they bifurcate. These two cells synapse with each other in the molecular layer.

Towards the end of the embryonic period, granule cell precursors are added from the rhombic lip, which then develop into a large number of granule cells in the EGL. Purkinje cells express Shh (which acts as a potent mitogenic signal to expand the granule cell progenitor population), while the granule cells express the appropriate receptors like patched and smoothened. 

Granule cells, as said before, develop from rhombic lip (also known as germinal trigone) which is formed at the superior and inferior edges of the medullary velum. The precursors generated next to the rim of the 4th ventricle migrate to the external granule layer, where cells actively proliferate into large numbers of granule cell progenies. The EGL acts as a secondary site of neurogenesis (up to 2nd year postnatally in humans).

Caudal/Inferior rhombic lip gives rise to pontine nuclei and the inferior olive. Neurons of these precerebellar nuclei migrate along various pathways (e.g. corpus pontobulbare) to their ultimate position in the brain stem.

Production of rhombic lip cells is regulated by MATH1 (mouse atonal homologue) which is a transcription factor. MATH1 -/- gives rise to a phenotype with no foliation, no internal granule layer and no pontine nuclei. Zic1/2 are also important to get correct rhombic lip associated cell fates.

Antagonism between the Notch and BMP signaling pathways regulates the differentiation of cerebellar progenitors throughout the period of cerebellar neurogenesis.

 

Migration of granule cells under Purkinje cells

The granule cells (which are initially superficial) form axons called parallel fibers in the mature cerebellum. They migrate past the Purkinje cells, along the processes of Bergmann glia cells to their deeper, definitive site, the internal granule layer.

Slcla3 in Bermann Glia

The parallel fibers then extend axons tangential to the cortical surface thus assuming the T-shape and later sprout dendrites in the granule layer. At the same time of migration, Purkinje cells enlarge and develop dendritic trees. The inner granule layer is formed by further proliferation and migration of the external germinal cells. Situated below the layer of Purkinje cells, this layer is the definitive granule layer of the cerebellar cortex. A transient layer known as “lamina dissecans” separates the IGL from the Purkinje cells. It is later filled with the migrating granule cells and eventually disappears.

Image 1: Bergmann Glia.

Image courtesy of http://commons.wikimedia.org/wiki/File:Slcla3_in_Bergmann_Glia.jpg.  This image is in the public domain and thus free of any copyright restrictions.